| Abstract | PURPOSE: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokinetic-pharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 micromol/L (t(C > 0.05-0.2)) predicts neutropenia. The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients. EXPERIMENTAL DESIGN: One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m(2)) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL*min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Semiphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data. RESULTS: One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel t(C > 0.05) was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively). Patients with paclitaxel t(C > 0.05) > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel t(C > 0.05) < 61.4 h (89.0 versus 61.9 weeks; P = 0.05). Paclitaxel t(C > 0.05) was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (C(max) and area under the concentration-time curve) was the best predictor for thrombocytopenia (P < 10(-4)). CONCLUSIONS: In this group of patients, paclitaxel t(C > 0.05) is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia. |
| Authors | Markus Joerger, Alwin D R Huitema, Dick J Richel, Christian Dittrich, Nikolas Pavlidis, Evangelos Briasoulis, Jan B Vermorken, Elena Strocchi, Andrea Martoni, Roberto Sorio, Henk P Sleeboom, Miguel A Izquierdo, Duncan I Jodrell, Hilary Calvert, Alan V Boddy, Harry Hollema, Regine Féty, Wjf J F Van der Vijgh, Georg Hempel, Etienne Chatelut, Mats Karlsson, Justin Wilkins, Brigitte Tranchand, Ad H G J Schrijvers, Christian Twelves, Jos H Beijnen, Jan H M Schellens
(Affiliation: Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands. markus.joerger at kssg.ch)
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| Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 13
Issue 21
Pg. 6410-8
(Nov 1 2007)
ISSN: 1078-0432 United States |
| PMID | 17975154
(Publication Type: Journal Article, Multicenter Study)
|
| Chemical References |
- Antineoplastic Agents
- Paclitaxel
- Carboplatin
|
| Topics |
- Antineoplastic Agents
(therapeutic use)
- Antineoplastic Combined Chemotherapy Protocols
(therapeutic use)
- Area Under Curve
- Carboplatin
(pharmacokinetics, pharmacology)
- Disease Progression
- Drug Design
- Europe
- Female
- Humans
- Kinetics
- Neutropenia
- Ovarian Neoplasms
(drug therapy, genetics, pathology)
- Paclitaxel
(pharmacokinetics, pharmacology)
- Predictive Value of Tests
- Thrombocytopenia
- Treatment Outcome
|
